Age-related macular degeneration (AMD) causes progressive impairment of central vision and is the leading cause of irreversible vision loss in older Americans (Swaroop A et al., 2007, Hum Mol Genet 16 Spec 2:R174-82). The most severe form of AMD involves neovascular/exudative (wet) and/or atrophic (dry) changes to the macula. Although the etiology of AMD remains largely unknown, implicated risk factors include age, ethnicity, smoking, hypertension, obesity and diet (Ambati J et al., 2003, Surv Opthalmol 48(3):257-93). Familial aggregation (Klaver C C et al., 1998, Arch Opthalmol 116(5):653-8), twin studies (Hammond C J et al., 2002, Opthalmology 109(4):730-6), and segregation analysis (Heiba I M et al., 1994, 11(1):51-67) suggest that there is also a significant genetic contribution to the disease. The candidate gene approach and genome-wide association studies have consistently implicated the complement factor H (CFH), third component of complement (C3) and second component of complement/factor B (C2/BF) genes, all members of the complement-mediated inflammatory cascade, as well as Age-Related Maculopathy Susceptibility 2 (ARMS2), a gene likely involved in mitochondria-associated pathways.
Much progress has been made in identifying and characterizing the genetic basis of AMD. In a remarkable example of the convergence of methods for disease gene discovery, multiple independent research efforts identified the Y402H variant in the complement factor H (CFH [(MIM 134370]) gene on chromosome 1q32 as the first major AMD susceptibility allele (Haines J L et al., 2005, Science 308(5720):419-21; Hageman G S et al., 2005, Proc Natl Acad Sci USA 102(20):7227-32; Klein R J et al., 2005, Science 308(5720):385-9; Edwards A O et al., 2005, Science 308(5720):421-4; Zareparsi S et al., 2005, Am J Hum Genet 77(1):149-53; Jakobsdottir J et al., 2005, Am J Hum Genet 77(3):389-407). While one of the studies was able to pinpoint CFH on the basis of a whole-genome association study (Klein R J et al., supra), most studies focused on the 1q32 region because it had consistently been implicated by several whole-genome linkage scans. More recently, disease associated haplotypes within the CFH gene have also been shown to be associated with AMD (Li M et al., 2006, Nat Genet 38(9):1049-54). A second genomic region with similarly consistent linkage evidence is chromosome 10q26, which was identified as the single most promising region by a recent meta-analysis of published linkage screens (Fisher S A et al., 2005, Hum Mol Genet 14(15):2257-64).
Two other studies have suggested specific AMD susceptibility genes located on chromosome 10q26. One used a combination of family-based and case-control analyses to implicate the PLEKHAl gene (pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 1 [MIM 607772]) and the predicted ARMS2 gene (Jakobsdottir J et al., supra). ARMS2 appears to be a mitochondrial membrane protein with unknown function (Kanda A et al., 2007, Proc Natl Acad Sci USA 104(41):16227-32). A second study using two independent case-control datasets concluded that the T allele of SNP rs10490924 in ARMS2, a coding change (Ala69Ser) in exon 1 of this gene, was associated with AMD (Rivera A et al., 2005, Human Mol Genet 14(210:3227-36). Both studies reported that the chromosome 10q26 variant confers an AMD risk similar in magnitude to that of the Y402H variant in CFH. A locus with less strong association, but reproducible association is the complement component 2 (C2) and Factor B (C2/BF) locus within the major histocompatability complex III locus found on chromosome 6. The L9H variant of BF and the E318D variant of C2, as well as a variant in intron 10 of C2 and the R32Q variant of BF, confer a significantly reduced risk of AMD (Gold B et al., 2006, Nat Genet 38(4):458-62). Similarly, a highly significant association with AMD and SNPs within the C3 gene on chromosome 19p13.3-p13.2, specifically rs2230199 (Arg80Gly), was established recently (Yates et al., 2007, N Engl J Med 357(6):553-61).
There is a continuing need in the art to identify individual genes that are involved in the pathogenesis of AMD and/or to identify particular functional alleles that are directly involved in the pathogenesis of AMD, as well as to identify the interaction of the genes with modifiable behaviors.